Are Scientists Closer to Discovering a Fountain of Youth?

International study kicked off by a prematurely aging boy provides insight into the mechanisms behind growing older

by Nikhil Swaminathan

December 21, 2006

ANDRIA RASILE ROBINSON & LAURA NIEDERNHOFER, UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE
The case of a 15-year-old Afghan boy with a rare genetic condition that caused him to age rapidly may help scientists unlock the mysteries how and why we age, bringing them closer to finding a way to halt or dramatically slow the aging process.

Physicians discovered that the boy, admitted to a Dutch hospital in the 1990s suffering from symptoms including hypertension, hearing and vision loss, kidney failure, anemia and sensitivity to light, had a mutation in a key gene responsible for the enzyme that is essential to the repair of DNA damage in cells. The genetic flaw caused him to age prematurely and die essentially of old age before completing puberty.

The teen's illness (now known as XPF-progeroid syndrome), when replicated in mice, allowed an international team of researchers to answer a fundamental question in the science of aging: Do we get old due to the accumulation of damage over our lifetimes or due to the genetic blueprint we inherit?

"What we say is [that] both are valid and that, in particular, damage to DNA contributes to aging," says Jan Hoeijmakers, a geneticist at the Erasmus Medical Center in Rotterdam, the Netherlands, and lead author of the study, which comprised teams from four different institutions in Europe and the U.S. "Damage accumulates ... but it is modulated by your genetic makeup. If you have better repair and/or slower metabolism, you age slower."

The boy, who Hoeijmakers observed years ago, had a defect in a gene known as XPF, whose enzyme combines with the protein coded by another gene called ERCC1 to form the complex XPF-ERCC1 endonuclease. The complex is needed to repair DNA damaged by exposure to ultraviolet light, x-rays, chemicals in food, cigarette smoke and other stimuli.

"Our own respiration and metabolism," Hoeijmakers says, "produce constantly reactive oxygen species and other chemicals that have a tendency to react with and damage all sorts of cellular components [including] ... our DNA." Damaged DNA leads to cell death or dysfunction and "over time you lose cells, cells and organs do not function so well anymore and you gradually age."

Hoeijmakers's team created transgenic mice that did not express ERCC1 in order to study the aging effects caused by its deficiency. The mutant mice physically showed some retardation during pre- and post-natal development, no growth after two weeks and, typically, died at four weeks of age.

The researchers compared the activity of thousands of genes in the liver of a 15-day-old mutant mouse to those in a normal mouse who lived two and a half years. The result? "The rapidly aging mice switched their activity from growth to maintenance and repair, up-regulating cellular defenses and down-regulating respiration and metabolism," Hoeijmakers says. "This also occurs upon natural aging, and if you [could] switch to this 'survival' mode early in life, you would live longer."

When humans switch to survival mode as they age, effects can include the dwindling of muscle mass and bone-density loss. When the researchers compared the genes that influence growth pathways in the mutant mouse and the aged mouse, they found a 95 percent correlation in gene expression.

"Because there were such high correlations between these pathways," says co-author Laura Neidernhofer of the University of Pittsburgh School of Medicine, "we are quite confident that DNA damage plays a significant role in promoting the aging process."

Richard Faragher, a biomolecular scientist at the University of Brighton in England, believes this study, which appears in this week's issue of Nature, is one of the 'ribs' of aging research," because it starts to link cellular mechanisms responsible for aging with effects on life span. "I think it will allow people to start thinking about the causal mechanisms of aging in a much more integrated way," he says, specifically, "what the mutation does to the cell, what the cell does to the tissue and what the tissue does to the organism."

Toward that end, Hoeijmakers and his team have started a small company called Dnage that is designed to find ways to slow aging and fight age-related disease. "If we would be able to reduce the induction of DNA damage by triggering the survival response [to lower metabolism and allow less damage] or by boosting repair or, perhaps, by adding protecting compounds in food or medication," he says, "the rate of DNA damage and consequently aging may be reduced."